Medications to USE WITH Medications to USE WITH CAUTION in the CAUTION in the

Management of TBIManagement of TBISusan M. Stickevers, MDSusan M. Stickevers, MD

Residency Program Director, Residency Program Director, Physical Medicine & Physical Medicine &

Rehabilitation Rehabilitation SUNY Stony Brook SUNY Stony Brook

Medications …Medications …

Can produce changes in …Can produce changes in … Mood Mood Cognition Cognition Perception Perception AttentionAttention ……in neurologically intact subjects ….in neurologically intact subjects ….

Psychiatric Side Effects of Psychiatric Side Effects of Commonly Used Commonly Used

Medications Medications Depression seen with Depression seen with

use of :use of : Amantidine – common at Amantidine – common at

standard dosesstandard doses Anticonvulsants – usually Anticonvulsants – usually

at higher blood levelsat higher blood levels Steroids / ACTH – Steroids / ACTH –

common at higher doses common at higher doses or drug withdrawalor drug withdrawal

Benzodiazepines Benzodiazepines Opiates Opiates Levodopa – risk Levodopa – risk

increases with prolonged increases with prolonged use use

Oral contraceptives Oral contraceptives

Metoclopramide – at Metoclopramide – at usual doses usual doses

Propanolol – at usual Propanolol – at usual dosesdoses

Antihypertensives – Antihypertensives – with many with many preparations preparations

Barbituates – common Barbituates – common Vinblastine - rareVinblastine - rare Asparaginase – Asparaginase –

common with higher common with higher dosesdoses

Cimetidine Cimetidine Ibuprofen – rare Ibuprofen – rare

Mania is Observed with Mania is Observed with Use of :Use of :

Baclofen, Baclofen, particularly with particularly with sudden withdrawalsudden withdrawal

Bromocriptine – sx Bromocriptine – sx may persist after may persist after drug is withdrawndrug is withdrawn

Captopril – sx may Captopril – sx may persist after drug persist after drug withdrawalwithdrawal

Steroids/ ACTHSteroids/ ACTH

Levodopa : in Levodopa : in elderly, elderly, particularly with particularly with prolonged use prolonged use

Antidepressants, Antidepressants, particularly in pts. particularly in pts. with bipolar with bipolar disorder disorder

Hallucinations May be Hallucinations May be Occur when the Following Occur when the Following

Drugs are Used :Drugs are Used : Amantidine – more Amantidine – more

common in elderlycommon in elderly Anticonvulsants – visual Anticonvulsants – visual

& auditory & auditory hallucinations hallucinations

Antihistamines – esp Antihistamines – esp with higher doseswith higher doses

Anticholinergics – Anticholinergics – usually with deliriumusually with delirium

Corticosteroids Corticosteroids Digitalis – at higher Digitalis – at higher

blood levels blood levels Indomethacin – esp in Indomethacin – esp in

elderlyelderly

Propanolol Propanolol Methylphenidate – Methylphenidate –

more likely in childrenmore likely in children Levodopa – more Levodopa – more

frequently in elderly frequently in elderly with increased doses with increased doses

Ketamine – can induce Ketamine – can induce a dissociative state a dissociative state

Cimetidine – usually Cimetidine – usually in elderly at increased in elderly at increased dosesdoses

Paranoia May Occur with Paranoia May Occur with Use of the Following :Use of the Following :

Bromocriptine – Bromocriptine – not dose relatednot dose related

Amphetamines – Amphetamines – may occur even at may occur even at low doseslow doses

Indomethacin – esp Indomethacin – esp in elderly patientsin elderly patients

Propanolol – may Propanolol – may occur at any dose occur at any dose

Asparaginase – Asparaginase – commonly causes commonly causes paranoiaparanoia

Sulindac Sulindac

Aggression May Occur with Aggression May Occur with Use of :Use of :

Bromocriptine – Bromocriptine – not dose related, not dose related, may persist may persist

Tranquilizers & Tranquilizers & Hypnotics – a Hypnotics – a release release phenomenon phenomenon

Levodopa – often Levodopa – often after dose increase after dose increase

Carbamazepine – Carbamazepine – esp in children & esp in children & adolescents adolescents

Digitalis – may be Digitalis – may be seen with higher seen with higher blood levels blood levels

Phenelzine Phenelzine

Nightmares Nightmares

Baclofen – usually Baclofen – usually after sudden after sudden withdrawal withdrawal

Ketamine – causes Ketamine – causes emotion lability, emotion lability, changes in body changes in body image, deliriumimage, delirium

Levodopa – often Levodopa – often after dose increaseafter dose increase

Pentazocine Pentazocine

Propanolol Propanolol Digitalis – Digitalis –

particularly with particularly with high drug levels high drug levels

Antidepressants – Antidepressants – particularly with particularly with nighttime dosing nighttime dosing

Amantidine Amantidine

Medications Can Impair Medications Can Impair Neurological Recovery…Neurological Recovery…

Assess all medications of patients Assess all medications of patients with TBI as medications may…with TBI as medications may…

Cause sedationCause sedation Produce memory dysfunctionProduce memory dysfunction Decrease overall arousal & ability to Decrease overall arousal & ability to

participate in therapyparticipate in therapy

Antihypertensives Antihypertensives

Centrally acting antihypertensives, such as Centrally acting antihypertensives, such as methyldopa, have a significantly sedating methyldopa, have a significantly sedating effecteffect

Clonidine is an alpha 2 agonist with central Clonidine is an alpha 2 agonist with central activity which may produce impaired activity which may produce impaired cognition –it may also be used for the cognition –it may also be used for the treatment of spasticitytreatment of spasticity

Both clonidine & prazocin (alpha 1 agonist) Both clonidine & prazocin (alpha 1 agonist) have been shown to reinstate deficits after have been shown to reinstate deficits after sensorimotor cortex ablation (Feeney & sensorimotor cortex ablation (Feeney & Sutton, 1987)Sutton, 1987)

Antihypertensives – Beta Antihypertensives – Beta BlockersBlockers

Lipophilic beta blockers that cross Lipophilic beta blockers that cross the blood – brain barrier (i.e. the blood – brain barrier (i.e. propanolol) are useful in the propanolol) are useful in the treatment of agitation, however….treatment of agitation, however….

These agents may also produce These agents may also produce significant sedation which interferes significant sedation which interferes with the rehabilitation process with the rehabilitation process

Calcium Channel Calcium Channel BlockersBlockers

A decrease in dopaminergic A decrease in dopaminergic transmission has been found with transmission has been found with use of calcium channel blockers in use of calcium channel blockers in experimental models experimental models

No direct effect of calcium channel No direct effect of calcium channel blockers on motor or cognitive blockers on motor or cognitive recovery has been established recovery has been established however in humanshowever in humans

Benzodiazepines Benzodiazepines

Exert their effects on GABA A receptor; Exert their effects on GABA A receptor; increasing the rate of chloride channel increasing the rate of chloride channel opening opening

Rapidly cross blood – brain barrier Rapidly cross blood – brain barrier Produce antegrade amnesia & anxiolysis Produce antegrade amnesia & anxiolysis Decrease new learning & memory Decrease new learning & memory Produce increased confusion & agitation in Produce increased confusion & agitation in

brain injured patients brain injured patients Their use in TBI patients is NOT Their use in TBI patients is NOT

recommendedrecommended

Gastrointestinal AgentsGastrointestinal Agents

Histamine 2 receptor blockers, such as :Histamine 2 receptor blockers, such as : CimetidineCimetidine RanitidineRanitidine Famotidine Famotidine Nizatidine …..Nizatidine ….. ……may have sedating potential in TBI may have sedating potential in TBI

patients and in the elderlypatients and in the elderly Use of PPI is suggested in lieu of H2 Use of PPI is suggested in lieu of H2

blockersblockers

Metoclopramide Metoclopramide Is commonly used to enhance GI motility Is commonly used to enhance GI motility It enhances gastric contraction, raises It enhances gastric contraction, raises

esophageal pressure, & promotes relaxation esophageal pressure, & promotes relaxation of the pylorus of the pylorus

Has significant D2 receptor antagonist Has significant D2 receptor antagonist effects & can produce impaired cognitive effects & can produce impaired cognitive responses responses

Extrapyramidal side effects can be seen Extrapyramidal side effects can be seen with use of this drug with use of this drug

Its use in TBI patients is NOT recommended Its use in TBI patients is NOT recommended –consider use of erythromycin instead–consider use of erythromycin instead

Neuroleptics Neuroleptics

Neuroleptics block dopamine in Neuroleptics block dopamine in addition to acting as cholinergic & addition to acting as cholinergic & adrenergic antagonists adrenergic antagonists

Use of dopaminergic antagonists is Use of dopaminergic antagonists is relatively contraindicated due to relatively contraindicated due to depletion of dopamine post brain injury depletion of dopamine post brain injury

Feeney has raised concerns that Feeney has raised concerns that neuroleptics impair motor & cognitive neuroleptics impair motor & cognitive recovery after TBI (Feeney et al, 1982)recovery after TBI (Feeney et al, 1982)

Neuroleptics Neuroleptics

Potential side effects include :Potential side effects include : Extrapyramidal symptoms Extrapyramidal symptoms Anticholinergic side effectsAnticholinergic side effects Lowered seizure threshold Lowered seizure threshold Neuroleptic malignant syndrome Neuroleptic malignant syndrome Detrimental effects on learning & Detrimental effects on learning &

memory memory

Neuroleptic Agents Neuroleptic Agents

The majority of these agents act at the The majority of these agents act at the D2 receptor D2 receptor

Rao et al, 1985 Rao et al, 1985 : a retrospective chart : a retrospective chart review of 26 TBI Patients in which 11 review of 26 TBI Patients in which 11 were treated with haldol revealed…were treated with haldol revealed… Significantly longer periods of post Significantly longer periods of post

traumatic amnesia, however… traumatic amnesia, however… The acute rehabilitation outcome did not The acute rehabilitation outcome did not

differ from those not treated with this differ from those not treated with this medicationmedication

Neuroleptic Agents Neuroleptic Agents

Patients with brain injury are more Patients with brain injury are more sensitive to the development of sensitive to the development of extrapyramidal side effects when extrapyramidal side effects when treated with typical antipsychotic treated with typical antipsychotic agents agents

( Rosebush & Stewart, 1989, Vincent et ( Rosebush & Stewart, 1989, Vincent et al, 1986, Wolf et al, 1989, Yassa et al, al, 1986, Wolf et al, 1989, Yassa et al, 1984)1984)

Atypical Antipsychotics Atypical Antipsychotics for TBI?for TBI?

There is a dearth of literature to There is a dearth of literature to guide treatment selection amongst guide treatment selection amongst the atypical antipsychotic drugs, the atypical antipsychotic drugs, despite extensive documentation of despite extensive documentation of the ill effects of the typical the ill effects of the typical antipsychotic agents ….antipsychotic agents ….

Atypical AntipsychoticsAtypical Antipsychotics

Clozapine is one of the newer agents Clozapine is one of the newer agents with both dopaminergic & with both dopaminergic & serotoninergic blocking properties serotoninergic blocking properties

Clozapine has action at both the D1 & Clozapine has action at both the D1 & D4 receptors, as well as the 5HT-1 site D4 receptors, as well as the 5HT-1 site

2/9 patients placed on this drug for 2/9 patients placed on this drug for psychosis post TBI developed seizures, psychosis post TBI developed seizures, 7/9 showed improved aggression, 7/9 showed improved aggression, fewer outbursts & fewer fewer outbursts & fewer hallucinations hallucinations (Michals et al, 1993)(Michals et al, 1993)

Clozapine (Clozaril) Clozapine (Clozaril)

Burke et al (1999)Burke et al (1999) Improvement in refractory psychotic Improvement in refractory psychotic

symptoms after TBI with clozapine use symptoms after TBI with clozapine use **Risk of seizures is increased** **Risk of seizures is increased** Risk of neutropenia and anemia warrants Risk of neutropenia and anemia warrants

monitoring CBC monitoring CBC Has greater anti-aggressive effects Has greater anti-aggressive effects

than other antipsychotic medications than other antipsychotic medications (Michals et al, 1993, Ratey, 1993)(Michals et al, 1993, Ratey, 1993)

Clozapine (Clozaril) Clozapine (Clozaril) Study Study N= 9 study subjects :7 controls N= 9 study subjects :7 controls

AggressiveAggressive TBI patients with psychotic TBI patients with psychotic symptoms or rage outbursts.symptoms or rage outbursts.

Marked decrease in aggression in 2 Marked decrease in aggression in 2 subjects, less bizarre behavior in 1, mild subjects, less bizarre behavior in 1, mild improvement in agitation and hallucination improvement in agitation and hallucination in 3, indeterminate response in 3. in 3, indeterminate response in 3.

Seizures developed in 2 study subjectsSeizures developed in 2 study subjects Dose : Clozapine 300–750 mg/d.Dose : Clozapine 300–750 mg/d.

Risperadone Risperadone

Risperadone : an atypical antipsychotic Risperadone : an atypical antipsychotic acts at the D2 and 5HT - 2 receptor acts at the D2 and 5HT - 2 receptor

Schreiber et al (1998) Schreiber et al (1998) : Successfully : Successfully used risperadone to treat delusions & used risperadone to treat delusions & sleep disturbance post TBIsleep disturbance post TBI

Successfully used to treat refractory Successfully used to treat refractory paranoid delusions & auditory paranoid delusions & auditory hallucinations after TBI with 4 mg QD hallucinations after TBI with 4 mg QD dosing dosing (Silver et al, 2005)(Silver et al, 2005)

Atypical Antipsychotics Atypical Antipsychotics

Olanzapine (Zyprexa) – More sedating than most Olanzapine (Zyprexa) – More sedating than most antipsychotics – avoid use in TBI patients if antipsychotics – avoid use in TBI patients if possible possible

Aripiprazole (Abilify) : Case Reports support the Aripiprazole (Abilify) : Case Reports support the use of Aripiprazole in TBI as well. Dose 10-15 mg use of Aripiprazole in TBI as well. Dose 10-15 mg QD to start, maximum dose 30 mg po QD QD to start, maximum dose 30 mg po QD

Quetiapine (Seroquel) – **one of the medications Quetiapine (Seroquel) – **one of the medications least likely to produce EPS in vulnerable patients, least likely to produce EPS in vulnerable patients, such as persons with TBI and Parkinsons Disease such as persons with TBI and Parkinsons Disease **** **Has a lower incidence of EPS than **Has a lower incidence of EPS than

risperadone** risperadone**

Quietapine (Seroquel) Quietapine (Seroquel) Study Study

Quetiapine - 7 TBI subjects at least 3 Quetiapine - 7 TBI subjects at least 3 months postinjurymonths postinjury

Pilot study open-label flexible dose Pilot study open-label flexible dose schedule schedule

84.5% reduction in Overt Aggression 84.5% reduction in Overt Aggression Scale–Modified and Clinical Global Scale–Modified and Clinical Global Impression Scale of Agitation and Impression Scale of Agitation and Aggression reduced from 4.14 to 2.29. Aggression reduced from 4.14 to 2.29.

Sedation reported in 3 patients. Sedation reported in 3 patients. Quetiapine dose 25–300 mg/d for 6 weeks.Quetiapine dose 25–300 mg/d for 6 weeks.

Ziprasidone (Geodon) Ziprasidone (Geodon)

Ziprasidone Ziprasidone : : Case series of 5 severe Case series of 5 severe head injury patients with head injury patients with posttraumatic amnesia and posttraumatic amnesia and agitation.agitation.

Agitated Behavior Scale decreased Agitated Behavior Scale decreased from 27.2 to 18.0 with Ziprasidone from 27.2 to 18.0 with Ziprasidone 40–80 mg/d for 2 weeks.40–80 mg/d for 2 weeks.

Atypical Antipsychotics Atypical Antipsychotics

Have lower potential for extrapyramidal Have lower potential for extrapyramidal effects effects

Their effect on cognitive outcome in brain Their effect on cognitive outcome in brain injury survivors is not well described injury survivors is not well described

Neuroleptics should not be considered Neuroleptics should not be considered agents of first choice in the treatment of agents of first choice in the treatment of behavioral disturbance in TBI patients, behavioral disturbance in TBI patients, but if patients are refractory to other but if patients are refractory to other treatments, trial of atypical antipsychotic treatments, trial of atypical antipsychotic agents should be considered agents should be considered

Anticonvulsants Anticonvulsants

Practice Parameters of the AAN, Practice Parameters of the AAN, AANS & AAPM&R : Anticonvulsant AANS & AAPM&R : Anticonvulsant prophylaxis is warranted for only one prophylaxis is warranted for only one week after closed head injury week after closed head injury ( Brain ( Brain Injury Special Interest Group, Injury Special Interest Group, AAPM&R, 1998)AAPM&R, 1998)

The role of anticonvulsant prophylaxis The role of anticonvulsant prophylaxis in patients with penetrating head in patients with penetrating head injury remains controversial injury remains controversial

Anticonvulsants & Anticonvulsants & Cognition in the TBI Cognition in the TBI

PatientPatient Long term use of phenytoin has been Long term use of phenytoin has been

reported to have adverse cognitive reported to have adverse cognitive effectseffects

Phenytoin has been described to have Phenytoin has been described to have more profound effects on cognition more profound effects on cognition than tegretol than tegretol (Gallassi et al, 1988) (Gallassi et al, 1988)

The deleterious effect of phenobarbital The deleterious effect of phenobarbital on cognition has been well described on cognition has been well described in the literature in the literature (Corbett et al, 1985)(Corbett et al, 1985)

Tegretol & Valproic Acid Tegretol & Valproic Acid

Glenn & Wrobleski have advocated use of Glenn & Wrobleski have advocated use of these agents for the management of post these agents for the management of post traumatic seizures in TBI patientstraumatic seizures in TBI patients

Controversy remains as to the relative Controversy remains as to the relative cognitive disturbance these agents can cognitive disturbance these agents can cause cause

Dikmen et al, 2000 : Valproic acid had no Dikmen et al, 2000 : Valproic acid had no adverse effect on cognition when adverse effect on cognition when administered for up to 12 months to TBI administered for up to 12 months to TBI survivors survivors

Valproic Acid for Post Valproic Acid for Post Traumatic Seizures?Traumatic Seizures?

Temkin, 1999 : Valproate did not Temkin, 1999 : Valproate did not demonstrate any efficacy in demonstrate any efficacy in preventing late post traumatic preventing late post traumatic seizures seizures

There was a non significant trend in There was a non significant trend in his study which demonstrated higher his study which demonstrated higher mortality during treatment with mortality during treatment with valproate valproate

Tegretol Tegretol

Smith et al, 1994 : Tegretol Smith et al, 1994 : Tegretol produces more cognitive & motor produces more cognitive & motor slowing than placebo in TBI patients slowing than placebo in TBI patients

Persinger, 2000 : 12/14 TBI patients Persinger, 2000 : 12/14 TBI patients treated with tegretol reported treated with tegretol reported improvements in confusion, improvements in confusion, depression, reduction in symptoms depression, reduction in symptoms of psychosis, improved attention & of psychosis, improved attention & ability to focus, ability to focus,

Second Generation Second Generation AnticonvulsantsAnticonvulsants

Gabapentin, lamictal, & topiramate are examples Gabapentin, lamictal, & topiramate are examples Often used as adjuvants agents for management Often used as adjuvants agents for management

of seizure disorder rather than monotherapy of seizure disorder rather than monotherapy Topiramate has been shown to adversely affect Topiramate has been shown to adversely affect

cognition in healthy young adults ( Martin et al, cognition in healthy young adults ( Martin et al, 1999)1999)

The effects of lamictal & gabapentin on TBI The effects of lamictal & gabapentin on TBI patients have not yet been fully described, patients have not yet been fully described, however…however…

Anticonvulsant polytherapy has been associated Anticonvulsant polytherapy has been associated with increased adverse neuropsychiatric with increased adverse neuropsychiatric reactions reactions (Reynolds & Trimble, 1985)(Reynolds & Trimble, 1985)

Opiates Opiates

Can produce sedation, Can produce sedation, hallucinations, decreased attention hallucinations, decreased attention in the TBI patient in the TBI patient

Use lowest possible doses, opt for Use lowest possible doses, opt for short acting agents if possible or short acting agents if possible or consider the use of opiate agonists / consider the use of opiate agonists / antagonists. antagonists.

““Go low and slow” with dose Go low and slow” with dose titration titration

Aminophylline Aminophylline

Can cause : Can cause : Agitation Agitation Lower seizure threshold Lower seizure threshold Hallucinations Hallucinations Avoid its use if possible Avoid its use if possible

AntiemeticsAntiemetics

Bind with dopamine receptors Bind with dopamine receptors Have the ability to have effects Have the ability to have effects

similar to the antipsychotic agents similar to the antipsychotic agents Avoid their use if possible Avoid their use if possible

Antidepressants Antidepressants

Avoid those with anticholinergic Avoid those with anticholinergic activity activity

Tricyclic antidepressants lower the Tricyclic antidepressants lower the seizure threshold seizure threshold

SSRIs are the drugs of choice for the SSRIs are the drugs of choice for the treatment of depression in the TBI treatment of depression in the TBI patient – trazadone may also be usedpatient – trazadone may also be used

Thanks for Your Thanks for Your Attention!Attention!